Effect of radical lymphadenectomy in colorectal cancer with para-aortic lymph node metastasis: a systematic review and meta-analysis

Background Colorectal cancer (CRC) with para-aortic lymph node metastasis (PALNM) is an intractable clinical situation, and the role of radical lymphadenectomy in the treatment of CRC with PALNM is still controversial. The aim of the current system review and meta-analysis is to evaluate the clinical efficacy and safety of radical lymphadenectomy in CRC patients with PALAN. Methods We performed a systematic search of PubMed, Embase, Cochrane Library and other online databases up to 31 October 2021. The clinical data including overall survival and postoperative complications were screened and analyzed after data extraction. Odds ratios (ORs) were applied to analyze these dichotomous outcomes with a fixed effects model. Results A total of 7 available retrospective clinical studies involving 327 patients were finally included. CRC patients with PALNM who underwent radical lymphadenectomy showed significantly overall survival (OR: 6.80, 95% CI: 3.46–13.38, P < 0.01; I2 = 0%) when compared to those who did not receive radical lymphadenectomy. Moreover, in terms of postoperative complications (OR: 0.71, 95% CI: 0.35–1.44, P = 0.48; I2 = 0%), there was no statistical difference between radical lymphadenectomy treatment and control groups. Conclusions The radical lymphadenectomy treatment has showed the expected clinical efficacy in prolonging overall survival time of CRC patients with PALAN. Moreover, the preemptive radical lymphadenectomy could not cause additional postoperative complications. Supplementary Information The online version contains supplementary material available at 10.1186/s12893-022-01631-x.


ROBINS
List co List co List co List co----interventions that could be different between intervention groups and that could impact on outcomes interventions that could be different between intervention groups and that could impact on outcomes interventions that could be different between intervention groups and that could impact on outcomes interventions that could be different between intervention groups and that could impact on outcomes Supplemental Is your aim for this study…? Is your aim for this study…? Is your aim for this study…? Is your aim for this study…?
to assess the effect of assignment to intervention to assess the effect of starting and adhering to intervention Specify the outcome Specify the outcome Specify the outcome Specify the outcome Specify which outcome is being assessed for risk of bias (typically from among those earmarked for the Summary of Findings table). Specify whether this is a proposed benefit or harm of intervention.
Specify the numerical result being assessed Specify the numerical result being assessed Specify the numerical result being assessed Specify the numerical result being assessed In case of multiple alternative analyses being presented, specify the numeric result (e.g. RR = 1.52 (95% CI 0.83 to 2.77) and/or a reference (e.g. to a table, figure or paragraph) that uniquely defines the result being assessed.

Preliminary consideration of confounders Preliminary consideration of confounders Preliminary consideration of confounders Preliminary consideration of confounders
Complete a row for each important confounding domain (i) listed in the review protocol; and (ii) relevant to the setting of this particular study, or which the study authors identified as potentially important.
"Important" confounding domains are those for which, in the context of this study, adjustment is expected to lead to a clinically important change in the estimated effect of the intervention. "Validity" refers to whether the confounding variable or variables fully measure the domain, while "reliability" refers to the precision of the measurement (more measurement error means less reliability). because adjustment makes no or minimal difference to the estimated effect of the primary parameter. Note that "no statistically significant association" is not the same as "not predictive".

Preliminary consideration of co Preliminary consideration of co Preliminary consideration of co Preliminary consideration of co----interventions interventions interventions interventions
Complete a row for each important co-intervention (i) listed in the review protocol; and (ii) relevant to the setting of this particular study, or which the study authors identified as important.
"Important" co-interventions are those for which, in the context of this study, adjustment is expected to lead to a clinically important change in the estimated effect of the intervention.
(i) Co-interventions listed in the review protocol

Co-intervention
Is there evidence that controlling for this cointervention was unnecessary (e.g. because it was not administered)?
Is presence of this co-intervention likely to favour outcomes in the experimental intervention or the comparator Can the true effect estimate be predicted to be greater or less than the estimated effect in the study because one or more of the important confounding domains was not controlled for? Answering this question will be based on expert knowledge and results in other studies and therefore can only be completed after all of the studies in the body of evidence have been reviewed. Consider the potential effect of each of the unmeasured domains and whether all important confounding domains not controlled for in the analysis would be likely to change the estimate in the same direction, or if one important confounding domain that was not controlled for in the analysis is likely to have a dominant impact.

Favours experimental / Favours comparator / Unpredictable
Bias in selection of participants into the study 2.1. Was selection of participants into the study (or into the analysis) based on participant characteristics observed after the start of intervention? If N/PN to 2.1: go to 2.4 This domain is concerned only with selection into the study based on participant characteristics observed after the start of intervention. Selection based on characteristics observed before the start of intervention can be addressed by controlling for imbalances between experimental intervention and comparator groups in baseline characteristics that are prognostic for the outcome (baseline confounding). Selection bias occurs when selection is related to an effect of either intervention or a cause of intervention and an effect of either the outcome or a cause of the outcome. Therefore, the result is at risk of selection bias if selection into the study is related to both the intervention and the outcome. If participants are not followed from the start of the intervention then a period of follow up has been excluded, and individuals who experienced the outcome soon after intervention will be missing from analyses. This problem may occur when prevalent, rather than new (incident), users of the intervention are included in analyses. It is in principle possible to correct for selection biases, for example by using inverse probability weights to create a pseudo-population in which the selection bias has been removed, or by modelling the distributions of the missing participants or follow up times and outcome events and including them using missing data methodology. However such methods are rarely used and the answer to this question will usually be "No".

Risk of bias judgement
See Table B Low / Moderate / Serious / Critical / NI Optional: What is the predicted direction of bias due to selection of participants into the study?
If the likely direction of bias can be predicted, it is helpful to state this. The direction might be characterized either as being towards (or away from) the null, or as being in favour of one of the interventions.

Favours experimental / Favours comparator / Towards null /Away from null / Unpredictable
Bias in classification of interventions 3.1 Were intervention groups clearly defined?
A pre-requisite for an appropriate comparison of interventions is that the interventions are well defined. Ambiguity in the definition may lead to bias in the classification of participants. For individual-level interventions, criteria for considering individuals to have received each intervention should be clear and explicit, covering issues such as type, setting, dose, frequency, intensity and/or timing of intervention. For population-level interventions (e.g. measures to control air pollution), the question relates to whether the population is clearly defined, and the answer is likely to be 'Yes'.

Y / PY / PN / N / NI
3.2 Was the information used to define intervention groups recorded at the start of the intervention?
In general, if information about interventions received is available from sources that could not have been affected by subsequent outcomes, then differential misclassification of intervention status is unlikely. Collection of the information at the time of the intervention makes it easier to avoid such misclassification. For population-level interventions (e.g. measures to control air pollution), the answer to this question is likely to be 'Yes'.
Y / PY / PN / N / NI 3.3 Could classification of intervention status have been affected by knowledge of the outcome or risk of the outcome?
Collection of the information at the time of the intervention may not be sufficient to avoid bias. The way in which the data are collected for the purposes of the NRSI should also avoid misclassification.

Risk of bias judgement
See Table B Low / Moderate / Serious / Critical / NI Optional: What is the predicted direction of bias due to measurement of outcomes or interventions?
If the likely direction of bias can be predicted, it is helpful to state this. The direction might be characterized either as being towards (or away from) the null, or as being in favour of one of the interventions.
Favours experimental / Favours comparator / Towards null /Away from null / Unpredictable

Bias due to deviations from intended interventions
If your aim for this study is to assess the effect of assignment to intervention, answer questions 4.1 and 4.2 4.1. Were there deviations from the intended intervention beyond what would be expected in usual practice?
Deviations that happen in usual practice following the intervention (for example, cessation of a drug intervention because of acute toxicity) are part of the intended intervention and therefore do not lead to bias in the effect of assignment to intervention.
Deviations may arise due to expectations of a difference between intervention and comparator (for example because participants feel unlucky to have been assigned to the comparator group and therefore seek the active intervention, or components of it, or other interventions). Such deviations are not part of usual practice, so may lead to biased effect estimates. However these are not expected in observational studies of individuals in routine care.
Y / PY / PN / N / NI 4.2. If Y/PY to 4.1: Were these deviations from intended intervention unbalanced between groups and likely to have affected the outcome?
Deviations from intended interventions that do not reflect usual practice will be important if they affect the outcome, but not otherwise. Furthermore, bias will arise only if there is imbalance in the deviations across the two groups.

NA / Y / PY / PN / N / NI
If your aim for this study is to assess the effect of starting and adhering to intervention, answer questions 4.3 to 4.6 4.3. Were important co-interventions balanced across intervention groups?
Risk of bias will be higher if unplanned co-interventions were implemented in a way that would bias the estimated effect of intervention. Cointerventions will be important if they affect the outcome, but not otherwise. Bias will arise only if there is imbalance in such co-interventions between the intervention groups. Consider the co-interventions, including any pre-specified co-interventions, that are likely to affect the outcome and to have been administered in this study. Consider whether these cointerventions are balanced between intervention groups.
Y / PY / PN / N / NI 4.4. Was the intervention implemented successfully for most participants?
Risk of bias will be higher if the intervention was not implemented as intended by, for example, the health care professionals delivering care during the trial. Consider whether implementation of the intervention was successful for most participants.
Y / PY / PN / N / NI 4.5. Did study participants adhere to the assigned intervention regimen?
Risk of bias will be higher if participants did not adhere to the intervention as intended. Lack of adherence includes imperfect compliance, cessation of intervention, crossovers to the comparator intervention and switches to another active intervention. Consider available information on the proportion of study participants who continued with their assigned intervention throughout follow up, and answer 'No' or 'Probably No' if this proportion is high enough to raise concerns. Answer 'Yes' for studies of interventions that are administered once, so that imperfect adherence is not possible.
We distinguish between analyses where follow-up time after interventions switches (including cessation of intervention) is assigned to (1)  It is possible to conduct an analysis that corrects for some types of deviation from the intended intervention. Examples of appropriate analysis strategies include inverse probability weighting or instrumental variable estimation. It is possible that a paper reports such an analysis without reporting information on the deviations from intended intervention, but it would be hard to judge such an analysis to be appropriate in the absence of such information. Specialist advice may be needed to assess studies that used these approaches.
If everyone in one group received a co-intervention, adjustments cannot be made to overcome this.

Risk of bias judgement
See Table  Optional: What is the predicted direction of bias due to deviations from the intended interventions?
If the likely direction of bias can be predicted, it is helpful to state this. The direction might be characterized either as being towards (or away from) the null, or as being in favour of one of the interventions.
Bias due to missing data 5.1 Were outcome data available for all, or nearly all, participants?
"Nearly all" should be interpreted as "enough to be confident of the findings", and a suitable proportion depends on the context. In some situations, availability of data from 95% (or possibly 90%) of the participants may be sufficient, providing that events of interest are reasonably common in both intervention groups. One aspect of this is that review authors would ideally try and locate an analysis plan for the study.
Y / PY / PN / N / NI 5.2 Were participants excluded due to missing data on intervention status?
Missing intervention status may be a problem. This requires that the intended study sample is clear, which it may not be in practice. Y / PY / PN / N / NI 5.3 Were participants excluded due to missing data on other variables needed for the analysis?
This question relates particularly to participants excluded from the analysis because of missing information on confounders that were controlled for in the analysis. This aims to elicit whether either (i) differential proportion of missing observations or (ii) differences in reasons for missing observations could substantially impact on our ability to answer the question being addressed. "Similar" includes some minor degree of discrepancy across intervention groups as expected by chance.
NA / Y / PY / PN / N / NI 5.5 If PN/N to 5.1, or Y/PY to 5.2 or 5.3: Is there evidence that results were robust to the presence of missing data?
Evidence for robustness may come from how missing data were handled in the analysis and whether sensitivity analyses were performed by the investigators, or occasionally from additional analyses performed by the systematic reviewers. It is important to assess whether assumptions employed in analyses are clear and plausible. Both content knowledge and statistical expertise will often be required for this. For instance, use of a statistical method such as multiple imputation does not guarantee an appropriate answer. Review authors should seek naïve (complete-case) analyses for comparison, and clear differences between complete-case and multiple imputation-based findings should lead to careful assessment of the validity of the methods used.

Risk of bias judgement
See Table  Low / Moderate / Serious / Critical / NI Optional: What is the predicted direction of bias due to missing data?
If the likely direction of bias can be predicted, it is helpful to state this. The direction might be characterized either as being towards (or away from) the null, or as being in favour of one of the interventions.

Favours experimental / Favours comparator / Towards null /Away from null / Unpredictable
Bias in measurement of outcomes 6.1 Could the outcome measure have been influenced by knowledge of the intervention received?
Some outcome measures involve negligible assessor judgment, e.g. all-cause mortality or non-repeatable automated laboratory assessments. Risk of bias due to measurement of these outcomes would be expected to be low.
Y / PY / PN / N / NI 6.2 Were outcome assessors aware of the intervention received by study participants?
If outcome assessors were blinded to intervention status, the answer to this question would be 'No'. In other situations, outcome assessors may be unaware of the interventions being received by participants despite there being no active blinding by the study investigators; the answer this question would then also be 'No'. In studies where participants report their outcomes themselves, for example in a questionnaire, the outcome assessor is the study participant. In an observational study, the answer to this question will usually be 'Yes' when the participants report their outcomes themselves. This question refers to differential misclassification of outcomes. Systematic errors in measuring the outcome, if present, could cause bias if they are related to intervention or to a confounder of the intervention-outcome relationship. This will usually be due either to outcome assessors being aware of the intervention received or to non-comparability of outcome assessment methods, but there are examples of differential misclassification arising despite these controls being in place.

Risk of bias judgement
See Table  Low / Moderate / Serious / Critical / NI Optional: What is the predicted direction of bias due to measurement of outcomes?
If the likely direction of bias can be predicted, it is helpful to state this. The direction might be characterized either as being towards (or away from) the null, or as being in favour of one of the interventions.

Bias in selection of the reported result
Is the reported effect estimate likely to be selected, on the basis of the results, from... 7.1. ... multiple outcome measurements within the outcome domain?
For a specified outcome domain, it is possible to generate multiple effect estimates for different measurements. If multiple measurements were made, but only one or a subset is reported, there is a risk of selective reporting on the basis of results.
Because of the limitations of using data from non-randomized studies for analyses of effectiveness (need to control confounding, substantial missing data, etc), analysts may implement different analytic methods to address these limitations. Examples include unadjusted and adjusted models; use of final value vs change from baseline vs analysis of covariance; different transformations of variables; a continuously scaled outcome converted to categorical data with different cut-points; different sets of covariates used for adjustment; and different analytic strategies for dealing with missing data. Application of such methods generates multiple estimates of the effect of the intervention versus the comparator on the outcome. If the analyst does not pre-specify the methods to be applied, and multiple estimates are generated but only one or a subset is reported, there is a risk of selective reporting on the basis of results.
Particularly with large cohorts often available from routine data sources, it is possible to generate multiple effect estimates for different subgroups or simply to omit varying proportions of the original cohort. If multiple estimates are generated but only one or a subset is reported, there is a risk of selective reporting on the basis of results.

Risk of bias judgement
See Table  Low / Moderate / Serious / Critical / NI Optional: What is the predicted direction of bias due to selection of the reported result?
If the likely direction of bias can be predicted, it is helpful to state this. The direction might be characterized either as being towards (or away from) the null, or as being in favour of one of the interventions.

Overall bias
Risk of bias judgement See Table D Low / Moderate / Serious / Critical / NI Optional: What is the overall predicted direction of bias for this outcome?
Favours experimental / Favours comparator / Towards null /Away from null / Unpredictable Table B. Reaching risk of bias judgements in ROBINS-I: pre-intervention and at-intervention domains

Judgement
Bias due to confounding Bias in selection of participants into study Bias in classification of interventions (i) Selection into the study may have been related to intervention and outcome; and The authors used appropriate methods to adjust for the selection bias; or (ii) Start of follow-up and start of intervention do not coincide for all participants; and (a) the proportion of participants for which this was the case was too low to induce important bias; or (b) the authors used appropriate methods to adjust for the selection bias; or (c) the review authors are confident that the rate (hazard) ratio for the effect of intervention remains constant over time.
(i) Intervention status is well defined; and (ii) Some aspects of the assignments of intervention status were determined retrospectively.
Serious risk of bias (the study has some important problems) (i) At least one known important domain was not appropriately measured, or not controlled for; or (ii) Reliability or validity of measurement of an important domain was low enough that we expect serious residual confounding.
(i) Selection into the study was related (but not very strongly) to intervention and outcome; and This could not be adjusted for in analyses; or (ii) Start of follow up and start of intervention do not coincide; and A potentially important amount of follow-up time is missing from analyses; and The rate ratio is not constant over time.
(i) Intervention status is not well defined; or (ii) Major aspects of the assignments of intervention status were determined in a way that could have been affected by knowledge of the outcome.
Critical risk of bias (the study is too problematic to provide any useful evidence on the effects of intervention) (i) Confounding inherently not controllable or (ii) The use of negative controls strongly suggests unmeasured confounding.
(i) Selection into the study was very strongly related to intervention and outcome; and This could not be adjusted for in analyses; or (ii) A substantial amount of follow-up time is likely to be missing from analyses; and The rate ratio is not constant over time.
(Unusual) An extremely high amount of misclassification of intervention status, e.g. because of unusually strong recall biases.
No information on which to base a judgement about risk of bias for this domain No information on whether confounding might be present.
No information is reported about selection of participants into the study or whether start of follow up and start of intervention coincide.
No definition of the intervention or no explanation of the source of information about intervention status is reported. Effect of assignment to intervention: (i) Any deviations from intended intervention reflected usual practice; or (ii) Any deviations from usual practice were unlikely to impact on the outcome.

Effect of starting and adhering to intervention:
The important co-interventions were balanced across intervention groups, and there were no deviations from the intended interventions (in terms of implementation or adherence) that were likely to impact on the outcome.
(i) Data were reasonably complete; or (ii) Proportions of and reasons for missing participants were similar across intervention groups; or (iii) The analysis addressed missing data and is likely to have removed any risk of bias.
(i) The methods of outcome assessment were comparable across intervention groups; and (ii) The outcome measure was unlikely to be influenced by knowledge of the intervention received by study participants (i.e. is objective) or the outcome assessors were unaware of the intervention received by study participants; and (iii) Any error in measuring the outcome is unrelated to intervention status.
There is clear evidence (usually through examination of a pre-registered protocol or statistical analysis plan) that all reported results correspond to all intended outcomes, analyses and subcohorts.
Moderate risk of bias (the study is sound for a nonrandomized study with regard to this domain but cannot be considered comparable to a well-performed randomized trial) Effect of assignment to intervention: There were deviations from usual practice, but their impact on the outcome is expected to be slight.
Effect of starting and adhering to intervention: (i) There were deviations from intended intervention, but their impact on the outcome is expected to be slight. or (ii) The important co-interventions were not balanced across intervention groups, or there were deviations from the intended interventions (in terms of implementation and/or adherence) that were likely to impact on the outcome; and The analysis was appropriate to estimate the effect of starting and adhering to intervention, allowing for deviations (in terms of implementation, adherence and co-intervention) that were likely to impact on the outcome.
(i) Proportions of and reasons for missing participants differ slightly across intervention groups; and (ii) The analysis is unlikely to have removed the risk of bias arising from the missing data.
(i) The methods of outcome assessment were comparable across intervention groups; and (ii) The outcome measure is only minimally influenced by knowledge of the intervention received by study participants; and (iii) Any error in measuring the outcome is only minimally related to intervention status.
(i) The outcome measurements and analyses are consistent with an a priori plan; or are clearly defined and both internally and externally consistent; and (ii) There is no indication of selection of the reported analysis from among multiple analyses; and (iii) There is no indication of selection of the cohort or subgroups for analysis and reporting on the basis of the results.
Serious risk of bias (the study has some important problems) Effect of assignment to intervention: There were deviations from usual practice that were unbalanced between the intervention groups and likely to have affected the outcome.
Effect of starting and adhering to intervention: (i) The important co-interventions were not balanced across intervention groups, or there were deviations from the intended interventions (in terms of implementation and/or adherence) that were likely to impact on the outcome; and (ii) The analysis was not appropriate to estimate the effect of starting and adhering to intervention, allowing for deviations (in terms of implementation, adherence and cointervention) that were likely to impact on the outcome.
(i) Proportions of missing participants differ substantially across interventions; or Reasons for missingness differ substantially across interventions; and (ii) The analysis is unlikely to have removed the risk of bias arising from the missing data; or Missing data were addressed inappropriately in the analysis; or The nature of the missing data means that the risk of bias cannot be removed through appropriate analysis.
(i) The methods of outcome assessment were not comparable across intervention groups; or (ii) The outcome measure was subjective (i.e. vulnerable to influence by knowledge of the intervention received by study participants); and The outcome was assessed by assessors aware of the intervention received by study participants; or (iii) Error in measuring the outcome was related to intervention status.
(i) Outcomes are defined in different ways in the methods and results sections, or in different publications of the study; or (ii) There is a high risk of selective reporting from among multiple analyses; or (iii) The cohort or subgroup is selected from a larger study for analysis and appears to be reported on the basis of the results.
Critical risk of bias (the study is too problematic to provide any useful evidence on the effects of intervention) Effect of assignment to intervention: There were substantial deviations from usual practice that were unbalanced between the intervention groups and likely to have affected the outcome.
Effect of starting and adhering to intervention: (i) There were substantial imbalances in important cointerventions across intervention groups, or there were substantial deviations from the intended interventions (in terms of implementation and/or adherence) that were likely to impact on the outcome; and (ii) The analysis was not appropriate to estimate the effect of starting and adhering to intervention, allowing for deviations (in terms of implementation, adherence and cointervention) that were likely to impact on the outcome.
(i) (Unusual) There were critical differences between interventions in participants with missing data; and (ii) Missing data were not, or could not, be addressed through appropriate analysis.
The methods of outcome assessment were so different that they cannot reasonably be compared across intervention groups.
(i) There is evidence or strong suspicion of selective reporting of results; and (ii) The unreported results are likely to be substantially different from the reported results.
No information on which to base a judgement about risk of bias for this domain No information is reported on whether there is deviation from the intended intervention.
No information is reported about missing data or the potential for data to be missing.
No information is reported about the methods of outcome assessment.
There is too little information to make a judgement (for example, if only an abstract is available for the study).